ABSTRACT Mitigation of tissue toxicity related to lung exposure to ionizing radiation is highly relevant to accidental or intentional exposure to high doses of radiation. The cytotoxic effects of ionizing radiation in normal lung parenchyma are mediated by the generation of reactive oxygen species (ROS) and are propagated by ROS-driven oxidative stress pointing towards a central role of tissue antioxidant defense. Preliminary data obtained from an exploratory R21 award showed that whole grain dietary flaxseed (FS) ameliorated the adverse effects of thoracic radiation by significantly enhancing overall mouse survival, blocking late phase lung fibrosis and modulating cell cycle, TGF-beta1 and apoptosis genes. Additionally, using acute models of pulmonary inflammation such as lung ischemia/reperfusion injury (related to transplantation injury) known to be mediated by generation of ROS, we were able to indicate that flaxseed via its lignan component, mitigated oxidative tissue damage and decreased lung inflammation. Mechanistic studies revealed a potent antioxidant effect of flaxseed mediated by the dual action of it lignan component in a) direct ROS scavenging and b) boosting of endogenous antioxidant enzyme defenses via activation of the Nrf2/ARE pathway. We, therefore, hypothesize that flaxseed lignans via their direct antioxidant, anti-inflammatory and anti- fibrotic action may be a novel therapeutic strategy to alleviate acute and chronic radiation-induced lung toxicity. Although we have only studied flaxseed and its lignan metabolites preventively in the context of radiation pneumonopathy, we believe that its use in mitigating post-exposure radiation injury will be equally effective. We have developed and characterized a mouse model of radiation pneumonopathy and in addition to using conventional methodologies to evaluate lung injury parameters we propose novel state of the art imaging methodologies using positron emission tomography (PET) and micro-computed tomography (CT) to perform longitudinal studies to evaluate lignan- mediated mitigation of lung toxicity in response to ionizing radiation. Goal 1 will focus on determining whether flaxseed lignans mitigate acute and chronic lung toxicity in mice related to external thoracic radiation while Goal 2 will focus on their role in mitigating internal thoracic radiation. The flaxseed lignan complex (FLC), is safe and can be administered to patients formulated in a tablet and is currently evaluated in clinical trials in the US and abroad so clinical translation is highly feasible.